JPS59511B2 - Method for producing bis[2-methyl-3-hydroxy-5-vinylpyrid-4-ylmethyl]disulfide - Google Patents

Method for producing bis[2-methyl-3-hydroxy-5-vinylpyrid-4-ylmethyl]disulfide

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Publication number
JPS59511B2
JPS59511B2 JP49067656A JP6765674A JPS59511B2 JP S59511 B2 JPS59511 B2 JP S59511B2 JP 49067656 A JP49067656 A JP 49067656A JP 6765674 A JP6765674 A JP 6765674A JP S59511 B2 JPS59511 B2 JP S59511B2
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Japan
Prior art keywords
methyl
hydroxy
compound
grams
disulfide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
JP49067656A
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Japanese (ja)
Other versions
JPS5040574A (en
Inventor
ピーター ドーン コンラツド
ガステイブ ヘイゼン ジヨージ
ユン シエン ツン
グレゴリー メリロ デイビツド
ビーング キーン リー トーマス
ジヨーンズ ハワード
スレツツインガー メイヤー
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Merck and Co Inc
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Merck and Co Inc
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Publication date
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of JPS5040574A publication Critical patent/JPS5040574A/ja
Publication of JPS59511B2 publication Critical patent/JPS59511B2/en
Expired legal-status Critical Current

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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
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    • C07D213/66—One oxygen atom attached in position 3 or 5 having in position 3 an oxygen atom and in each of the positions 4 and 5 a carbon atom bound to an oxygen, sulphur, or nitrogen atom, e.g. pyridoxal
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
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    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Description

【発明の詳細な説明】 本発明は新規なメルカプトアルキルピリジン誘導体の製
法に関し、更に詳しくはビス〔２−メチル−３−ヒドロ
キシ−５−ビニルピリジル−４−メチル〕ジスルフイド
の製法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing novel mercaptoalkylpyridine derivatives, and more particularly to a method for producing bis[2-methyl-3-hydroxy-5-vinylpyridyl-4-methyl]disulfide.

本発明の出発化合物は一般に既知のピリジン誘導体より
製する。The starting compounds of the invention are generally prepared from known pyridine derivatives.

６位に遊離のα−メルカプトアルキル基を持ち、α−メ
ルカプトアルキル基がヒドロキシル基に隣）接している
この出発化合物は対応するα−ヒドロキシアルキル化合
物をアルカリ金属ヒドロキサイド（例えば水酸化ナトリ
ウム、水酸化カリウム）を含有する低級アルカノール（
エタノールが良好）中で溶かし、この溶液を二硫化炭素
と反応せしめ、５『Ｃ〜還流温度で２〜８時間加熱し、
次に冷却混合物を酸性化する事により容易に製すること
ができる。This starting compound has a free α-mercaptoalkyl group in the 6-position, with the α-mercaptoalkyl group adjacent to the hydroxyl group. lower alkanols (potassium oxide) containing
This solution is reacted with carbon disulfide, heated at 5°C to reflux temperature for 2 to 8 hours,
It can then be easily produced by acidifying the cooled mixture.

単離は濃縮、溶媒抽出の如き基本法で出来る。またピリ
ジン核上の位置にかかわりなく遊離のα−メルカプトア
ルキル基を作る他の方法は前もつて製造したチオ化合物
から保護基を除去する方法で作ることができる。Isolation can be accomplished by basic methods such as concentration and solvent extraction. Another method for producing a free α-mercaptoalkyl group irrespective of its position on the pyridine nucleus is to remove a protecting group from a previously prepared thio compound.

例えばＳ−ベンゾイルの如きＳ−アシル化合物は希アル
カリで室温〜７５℃でケン化する如き加水分解法により
遊離のメルｉカプトに変換される。種々の位置のメルカ
プトアルキル基は又、対応するヒドロキシアルキル基を
チオニルクロライド又は濃臭化水素酸と５『Ｃ〜還流温
度で１〜４時間加熱してクロロメチル、又はブロモメチ
ルに変換し、出来たハロメチル基を下記の２種の方法の
いずれかで反応して製することができる。For example, S-acyl compounds such as S-benzoyl are converted to free mercapto by hydrolysis methods such as saponification with dilute alkali at room temperature to 75°C. Mercaptoalkyl groups at various positions can also be prepared by converting the corresponding hydroxyalkyl group to chloromethyl, or bromomethyl, by heating with thionyl chloride or concentrated hydrobromic acid at 5°C to reflux temperature for 1 to 4 hours. It can be produced by reacting a halomethyl group with either of the following two methods.

すなわち（ａ）水溶液中のノ和メチル化合物をエチルカ
リウムキサントゲネートの如き低級アルキルアルカリ金
属キサントゲネートと５〜１０℃で１〜４日間反応せし
め、キサンテート生成物をエーテル等の溶媒で抽出し、
リチウムアルミニウムハイドライド又はナトリウムボロ
ハイドライドで還元する。That is, (a) a methyl compound in an aqueous solution is reacted with a lower alkyl alkali metal xanthogenate such as ethyl potassium xanthogenate at 5 to 10°C for 1 to 4 days, and the xanthate product is extracted with a solvent such as ether. ,
Reduce with lithium aluminum hydride or sodium borohydride.

あるいはまたキサンテートを水酸化カリウ ム又は水酸
化ナトリウムの如きアルコール性アルカリ水溶液と５０
℃〜還流温度で加熱せしめ、メルカプトに変える事が出
来る。（ｂ）ハロメチル化合物をメタノール等の低級ア
ルカノール中チオ尿素と５０℃一還流温度で１〜４時間
加熱する。Alternatively, the xanthate may be mixed with an aqueous alcoholic alkali solution such as potassium hydroxide or sodium hydroxide for 50 min.
It can be converted to mercapto by heating from °C to reflux temperature. (b) A halomethyl compound is heated with thiourea in a lower alkanol such as methanol at 50°C and reflux temperature for 1 to 4 hours.

次にイソチオウレイドを水又はエタノールの如き低級ア
ルカノール中に水酸化カリウム又は水酸化ナトリウムの
如きアルカリ金属ヒドロキサイドを含ませたものの中で
窒素の如き不活性気体中で５０℃〜還流温度に加熱する
。他には、チオウレイドはリチウムアルミニウムハイド
ライド又はリチウムボロハイドライドと前述の如く還元
する。またその製造方法は次の如く示される。The isothioureide is then heated in water or a lower alkanol such as ethanol with an alkali metal hydroxide such as potassium hydroxide or sodium hydroxide under an inert gas such as nitrogen from 50 DEG C. to reflux. Alternatively, thiouraides are reduced with lithium aluminum hydride or lithium borohydride as described above. Further, the manufacturing method thereof is shown as follows.

出発化合物の１つであるメルカブトアルキル化合物のブ
ンテ（Ｂｕｎｔｅ）塩は対応するクロロ一又はブロモメ
チル化合物とナトリウムチオスルフエートとを水性アル
コール中５０℃〜環流温度で数分〜２時間加熱して製す
る。One of the starting compounds, the Bunte salt of a mercabutoalkyl compound, is prepared by heating the corresponding chloro-mono- or bromomethyl compound and sodium thiosulfate in aqueous alcohol at 50°C to reflux for several minutes to 2 hours. make

これらのブンテ（Ｂｕｎｔｅ）塩は新しい治療法におい
て有益であり、本発明の対称ジスルフイドへの中間体と
して利用性があるほか、非対称ジスルフイドまたは遊離
のメルカプトメチル化合物への中間体としても利用性が
ある。These Bunte salts are useful in new therapeutics and have utility as intermediates to the symmetric disulfides of the present invention, as well as to asymmetric disulfides or free mercaptomethyl compounds. .

本発明はジスルフイドニ量体のうち特に対称二量体の製
造方法にあり、それらの代表的実際態様は次の通り、（
１）対応する単量体の希水酸化アンモニウム水中に２０
〜５０℃で１５〜３０時間空気を導入するか、又は２０
−５０℃で有機溶媒中１−４日間空気を導入して酸化せ
しめる。The present invention particularly relates to a method for producing a symmetric dimer among disulfide dimers, and typical embodiments thereof are as follows: (
1) 20% of the corresponding monomer in dilute ammonium hydroxide water
Introducing air for 15-30 hours at ~50°C or
Oxidation is carried out in an organic solvent at −50° C. for 1 to 4 days by introducing air.

（２）単量体をｍ−クロロ過安息香酸過酢酸、過フタル
酸、ナトリウムヒポクロライト、ヨード、過酸化水素の
如き過酸と水溶液中、０−１５℃で酸化する。(2) Oxidize the monomer with a peracid such as m-chloroperbenzoic acid peracetic acid, perphthalic acid, sodium hypochlorite, iodine, hydrogen peroxide in aqueous solution at 0-15°C.

（３） ブンテ（Ｂｕｎｔｅ）塩を当量の２−メチル−
３−ヒドロキシ−４−メルカプトメチル−５−ビニルピ
リジンの如きメルカプトメチルピリジンと共に、水酸化
ナトリウム、水酸化カリウムの如きアルカリ金属ヒドロ
キサイド水溶液と２０ア−１００℃で混合して得る。(3) Bunte salt with an equivalent amount of 2-methyl-
It is obtained by mixing mercaptomethylpyridine such as 3-hydroxy-4-mercaptomethyl-5-vinylpyridine with an aqueous alkali metal hydroxide solution such as sodium hydroxide or potassium hydroxide at 20°C to 100°C.

本発明の方法で得られるジスルフイドは最終生成物のみ
ならず、分子中の他の官能基を扱う間、メルカプト基を
保護する都合のよい手段としてよく用いられる。The disulfide obtained by the process of the invention is often used as a convenient means of protecting the mercapto group while handling other functional groups in the molecule as well as the final product.

この場合単量体は還元して得る。有益な還元系としては
エーテル中リチウムアルミニウムハイドライドと室温で
１〜２０時間、塩酸中の匣鉛、酢酸中の岨鉛、塩水中の
スズ等である。最終生成物としても特に有益な保護基と
しても有益である誘導体の他の型は（それらがヒドロキ
シル基にも隣接のヒドロキシメチル、叉はメルカプトメ
チル基にも結合しているからである）環状ケタール又は
アセタールである。これらは例えば３−ヒドロキシ−４
−メルカプトメチル化合物をアセトン又はベンズアルデ
ヒドの如きカルボニル化合物と塩化水素ガスを飽和させ
−５カ−＋５℃で２〜６時間反応させて製する。本発明
の化合物は、リウマチ様関節炎用として経口的に、局所
的に、非経口的に、従来の非毒性薬剤的に有益な担体、
賦形薬、補助薬を含む投与単位形で吸入スプレー又は直
腸内に投与できる。In this case, the monomer is obtained by reduction. Useful reducing systems include lithium aluminum hydride in ether for 1 to 20 hours at room temperature, lead in hydrochloric acid, lead in acetic acid, tin in brine, and the like. Other types of derivatives that are particularly useful as final products and as protecting groups (because they are attached to both the hydroxyl group and the adjacent hydroxymethyl or mercaptomethyl group) are cyclic ketals. Or it is an acetal. These are for example 3-hydroxy-4
A -mercaptomethyl compound is prepared by reacting a carbonyl compound such as acetone or benzaldehyde with hydrogen chloride gas at -5°C for 2 to 6 hours at +5°C. The compounds of the present invention can be administered orally, topically, parenterally for use in rheumatoid arthritis, with conventional non-toxic pharmaceutically beneficial carriers,
It can be administered by inhalation spray or rectally in dosage unit form containing excipients and adjuvants.

ここで用いた非経口的という言葉は皮下注射、静脈内、
筋肉内、胸骨内、関節内注射、又は注入法を意味する。
マウス、ラツト、馬、犬、ネコ、等の温血動物の治療用
のほか、本発明の化合物は人間の治療にも効果的である
。例えば一日に体重１キログラムにつき０．５ミリグラ
ム〜１４０ミリグラムの量の投与が上述の症状の治療に
有効である（患者一日につき２５ミリグラム〜７グラム
）。The term parenteral used here refers to subcutaneous injection, intravenous,
Refers to intramuscular, intrasternal, intraarticular injection, or infusion techniques.
In addition to being used in the treatment of warm-blooded animals such as mice, rats, horses, dogs, cats, etc., the compounds of the present invention are also effective in the treatment of humans. For example, doses of 0.5 milligrams to 140 milligrams per kilogram of body weight per day are effective in treating the above-mentioned conditions (25 milligrams to 7 grams per patient per day).

例えば炎症は一日に体重１キログラムにつき化合物を０
．１〜５０ミリグラム投与すると効果的に治療出来、抗
一発熱、鎮痛効果が明白である。（患者一日につき５ミ
リグラム〜３，５グラム）、一日に体重１キログラムに
つき約１ミリグラム〜約１５ミリグラムの投与量で大へ
ん効果的な結果を得る（患者１日につき５０ミリグラム
〜１グラム）。単一投与形を作るため担体と合併する活
性成分の量は治療宿主、投与する形態に依存して変化す
る。For example, inflammation requires 0 compounds per kilogram of body weight per day.
．． Administering 1 to 50 milligrams can effectively treat the drug, with obvious antipyretic and analgesic effects. (5 milligrams to 3.5 grams per patient per day), with most effective results obtained at doses of about 1 milligram to about 15 milligrams per kilogram of body weight per day (50 milligrams to 1 gram per kilogram of body weight per patient per day). ). The amount of active ingredient that may be combined with the carrier to produce a single dosage form will vary depending on the host treated and the mode of administration.

例えば人間の経口投与のための剤形は全組成物の５〜９
５パーセントに変化するような適当で都合のよい担体の
量と混合した活性剤、５ミリグラム〜５グラムを含む。
投与単位形は一般に活性成分を２５ミリグラム〜５００
ミリグラムを含む。しかし多くの患者に対する投与量は
用いた化合物の活性、年令、体重、健康状態、性別、食
事、投与時間、投与経路、排泄速度、併用薬品、治療を
行う病気の程度等に依存する事は理解されよう。次に本
発明の新規化合物の製造を実施例により更に詳しく説明
する。尚原料化合物の製造例を併せて参考例として示す
。実施例 １ ビス〔２−メチル−３−ヒドロキシ−５−ビニル−４−
ピリジルメチル〕ジスルフイド２−メチル−３−ヒドロ
キシ−４−メルカブトメチル一５−ビニルピリジン塩酸
塩（９グラム）を５０ミリリツトルの水に溶かし２規定
水酸化アンモニウムで処理してＰＨ９とする。For example, a dosage form for oral administration to humans may contain 5-9% of the total composition.
5 milligrams to 5 grams of active agent mixed with a suitable convenient amount of carrier varying from 5 percent.
Dosage unit forms generally contain between 25 milligrams and 500 milligrams of active ingredient.
Contains milligrams. However, the dosage for most patients depends on the activity of the compound used, age, body weight, health condition, sex, diet, administration time, administration route, excretion rate, concomitant drugs, and the severity of the disease being treated. be understood. Next, the production of the novel compound of the present invention will be explained in more detail with reference to Examples. Note that production examples of raw material compounds are also shown as reference examples. Example 1 Bis[2-methyl-3-hydroxy-5-vinyl-4-
Pyridylmethyl] disulfide 2-methyl-3-hydroxy-4-mercabutomethyl-5-vinylpyridine hydrochloride (9 grams) was dissolved in 50 milliliters of water and treated with 2N ammonium hydroxide to pH 9.

この溶液に２４時間空気を導入する。沈澱したビス〔２
−メチル−３−ヒドロキシ−５−ビニル−４−ピリジル
メチル〕ジスルフイドを▲取し乾燥する。融点１７８−
１８０ル（分解）。実施例 ２ ビス〔２−メチル−３−ヒドロキシ−５−ビニル−４−
ピリジルメチル〕ジスルフイド２−メチル−３−ヒドロ
キシ−４−メルカプトメチル−５−ビニルピリジン塩酸
塩（４．３６グラム）を窒素気流下２−７℃で水４０ミ
リリツトルに溶かす。Air is introduced into this solution for 24 hours. Precipitated bis [2
-Methyl-3-hydroxy-5-vinyl-4-pyridylmethyl] disulfide is removed and dried. Melting point 178-
180 ru (disassembled). Example 2 Bis[2-methyl-3-hydroxy-5-vinyl-4-
Pyridylmethyl] disulfide 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine hydrochloride (4.36 grams) is dissolved in 40 milliliters of water at 2-7°C under nitrogen flow.

この溶液に２．０ミリリツトルの３０パーセント過酸化
水素水を２分以上で加える。この間温度を２−７℃に保
つ。３０分間、この温度で攪拌した後、混合物を沢過し
▲液を窒素気流下、過剰の炭酸水素ナトリウム飽和溶液
と２℃で１０分間攪拌する。Add 2.0 milliliters of 30 percent hydrogen peroxide to this solution over 2 minutes. During this time the temperature is maintained at 2-7°C. After stirring at this temperature for 30 minutes, the mixture is filtered and the solution ▲ is stirred with excess saturated sodium bicarbonate solution at 2° C. for 10 minutes under a nitrogen stream.

混合物をすばやくｐ過し、▲過物を２×４０ミリリツト
ルのアセトニトリルで洗浄する。固体を五酸化リンで乾
燥して１．５グラムのビス〔２−メチル−３−ヒドロキ
シ−５−ビニルー４−ピリジルメチル〕ジスルフイド、
融点〉３００ピを与える。モノハイドレートの融点１７
８−１８０℃ｏ実施例 ３ ビス〔２−メチル−３−ヒドロキシ−５−ビニルピリジ
ル−４−メチル〕ジスルフイド２−メチル−３−ヒドロ
キシ−４−メルカプトメチルピリジンのブンテ（Ｂｕｒ
ｌｔｅ）塩（２．６グラム）を１０パーセント（Ｗ／Ｖ
）水酸化ナトリウム水溶液１６ミリリツトル中の１．９
グラムの２メチル−３−ヒドロキシ−４−メルカプトメ
チル５−ビニルピリジンの溶液に溶かす。The mixture is quickly filtered and the filtrate washed with 2 x 40 milliliters of acetonitrile. The solid was dried over phosphorous pentoxide to yield 1.5 grams of bis[2-methyl-3-hydroxy-5-vinyl-4-pyridylmethyl] disulfide,
Gives a melting point of >300 pi. Melting point of monohydrate 17
Example 3 Bis[2-methyl-3-hydroxy-5-vinylpyridyl-4-methyl]disulfide 2-methyl-3-hydroxy-4-mercaptomethylpyridine Bur
lte) salt (2.6 grams) at 10 percent (W/V
) 1.9 in 16 ml of sodium hydroxide aqueous solution
grams of 2methyl-3-hydroxy-4-mercaptomethyl 5-vinylpyridine.

希塩酸でＰＨを６にし、沈澱を▲過して水洗及びアセト
ン、エーテルで洗浄する。これを乾燥しビス〔２−メチ
ル−３−ヒドロキシ−５−ビニルピリジル−４一メチル
〕ジスルフイドを与える。参考例 １ ２−メチル−３−ヒドロキシ−４−メルカプトメチル−
５−ビニルピリジン塩酸塩工程Ａ：２−メチル−３−ヒ
ドロキシ−４−ヒドロキシメチル−５−ビニルピリジン
の３・４αジ一０−イソプロピリデン誘導体の作製テト
ラヒドロフラン（３００ミリリツトル）中のトリフエニ
ルメチルホスホニウムブロマイド（４２．７グラム、０
．１２モル）の攪拌懸濁液中に６７ミリリツトルのｎ−
ブチルリチウム（ヘキサン中１．９モル）を窒素気流中
で加える。The pH is adjusted to 6 with dilute hydrochloric acid, and the precipitate is filtered and washed with water, acetone, and ether. This is dried to give bis[2-methyl-3-hydroxy-5-vinylpyridyl-4-methyl]disulfide. Reference example 1 2-methyl-3-hydroxy-4-mercaptomethyl-
5-Vinylpyridine hydrochloride Step A: Preparation of 3,4α di-10-isopropylidene derivative of 2-methyl-3-hydroxy-4-hydroxymethyl-5-vinylpyridine Triphenylmethylphosphonium in tetrahydrofuran (300 milliliters) Bromide (42.7 grams, 0
．． 67 ml of n-
Butyl lithium (1.9 mol in hexane) is added under a stream of nitrogen.

この攪拌溶液にテトラヒドロフラン（３００ミリリツト
ル中の２−メチル−３−ヒドロキシ−４−ヒドロキシメ
チル−５−ホルミルピリジン、３・４α−ジ一Ｏ−イソ
プロピリデン誘導体（２４．７グラム、０．１１９モル
）の溶液を１時間以上で滴加する。反応を室温で１時間
続け、次に４時間還流する。溶液をまず初めに、ふつう
のポンプ真空下で留去し、次に高真空下３０−５０℃で
留去乾燥する。赤色油状生成物を４００ミリリツトルの
エーテル中にて粉砕し、固体のトリフエニルホスフイン
オキサイドを▲過する（１７．０グラム）。エーテル戸
液を２×２００ミリリツトルの飽和ナトリウムビサルフ
アイト溶液で抽出する。これを留去乾燥し赤黄色油状物
を得る。生成物を次の工程で用いる。工程Ｂ：２−メチ
ル−３−ヒドロキシ−４−ヒドロキシメチル−５−ビニ
ルピリジン塩酸塩の作製上で得た油状物（２５グラム、
０．１２２モル）の溶液を２．５規定塩酸（５００ミリ
リツトル）及びアセトン（５００ミリリツトル）中で窒
素気流下１．５時間、攪拌還流を行う。To this stirred solution was added tetrahydrofuran (2-methyl-3-hydroxy-4-hydroxymethyl-5-formylpyridine, 3,4α-di-O-isopropylidene derivative (24.7 grams, 0.119 mol) in 300 milliliters). is added dropwise over 1 hour. The reaction is continued for 1 hour at room temperature and then refluxed for 4 hours. The solution is first distilled off under normal pump vacuum and then under high vacuum at 30-50 °C. Evaporate to dryness at °C. The red oil product is triturated in 400 milliliters of ether and filtered to remove solid triphenylphosphine oxide (17.0 grams). The ether solution is diluted with 2 x 200 milliliters of saturation. Extract with sodium bisulfite solution. This is evaporated to dryness to give a red-yellow oil. The product is used in the next step. Step B: 2-Methyl-3-hydroxy-4-hydroxymethyl-5-vinyl The oil obtained in the preparation of pyridine hydrochloride (25 grams,
A solution of 0.122 mol) was stirred and refluxed in 2.5N hydrochloric acid (500 ml) and acetone (500 ml) under a nitrogen atmosphere for 1.5 hours.

アセトンを留去して９０℃にまでし、溶液を冷却し酢酸
エチル（３×４００ミリリツトル）で抽出する。水層を
過剰の飽和炭酸水素ナトリウム溶液（７００ミリリツト
ル）中に注入する。水層を酢酸エチル（１×４００ミリ
リツトル）で抽出する。The acetone is distilled off to 90° C., the solution is cooled and extracted with ethyl acetate (3×400 milliliters). The aqueous layer is poured into excess saturated sodium bicarbonate solution (700 milliliters). The aqueous layer is extracted with ethyl acetate (1 x 400 milliliters).

有機溶媒を乾燥（ＭｇＳＯ４）し、▲過、留去して酢酸
エチルで再結晶して無色結晶を与える。融点１６４−１
６６結、９．４グラム。工程Ｃ：２−メチル−３−ヒド
ロキシ−４−メルカプトメチル−５−ビニルピリジン塩
酸塩の作製窒素ガス導入管、温度計、コンデンサーの上
部に滴加ロードを付けた１リツトルの３径フラスコに９
０パーセントエタノール５３０ミリリツトル、ＮａＯＨ
５３．４グラムを加える。The organic solvent is dried (MgSO4), filtered and evaporated, and recrystallized from ethyl acetate to give colorless crystals. Melting point 164-1
66 knots, 9.4 grams. Step C: Preparation of 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine hydrochloride Into a 1-liter 3-diameter flask equipped with a nitrogen gas introduction tube, a thermometer, and a dropping load on the top of the condenser,
0% ethanol 530ml, NaOH
Add 53.4 grams.

溶液が出来たら、工程Ｂの生成物５０グラムを加える。
この溶液に（Ｎ２ガス下）１０−１５をで攪拌下１／２
時間以上かけて、３０ミリリツトルのＣＳ２を滴加する
。出米た混合物を、次に２０℃で１／２時間攪拌し、次
に１５℃に冷却しさらにＣＳ２２Ｏミリリツトルを滴加
して４時間還流する。次に混合物を１『Ｃに冷却しＰＨ
が２になるまで濃塩酸を加える（約８０ミリリツトル必
要）。混合物を氷浴中で一夜放置する。減圧下濃縮し（
浴温２０氷）エタノールを除去する。出来た物質を１リ
ツトルの水と１２０グラムのＮａＨＣＯ３の冷却攪拌懸
濁液に（Ｎ２ガス下）加える。有機物を３×３００ミリ
リツトルの酢酸エチルで抽出する（出米るだけ空気を除
外する）。合併した抽出液をＭｇＳＯ４で乾燥する。こ
れを▲過し、減圧濃縮する。残渣を約１キログラムのＳ
ｉＯ２（Ｂａｋｅｒ）と溶出液として酢酸エチルを用い
てクロマトグラフイ一を行い精製する。対応する分画（
Ｔｌｃ−ＥｔＯＡｃ展開により決定）を合併し適当な量
にまで濃縮し白色結晶の遊離塩基を与える。最初の収獲
物融点１１５一１１７塩（３３グラム）、第２収獲物、
融点１１４−１１６グ（６グラム）元素分析 Ｃ９Ｈｌ
ｌＮＯＳとして、 計算値：Ｃｌ５９．６６：Ｈｌ６．ｌ２：Ｎｌ７．３３
；Ｓｌｌ７，７実測値：Ｃｌ５９．６４；Ｈｌ６．３５
；Ｎｌ７．２６：Ｓｌｌ７．３Ｏこれを次の方法で塩酸
塩に変える。Once the solution is formed, add 50 grams of the product from Step B.
To this solution (under N2 gas) add 10-15 liters of water under stirring.
Add 30 milliliters of CS2 dropwise over a period of time. The resulting mixture is then stirred at 20° C. for 1/2 hour, then cooled to 15° C. and further milliliters of CS22O are added dropwise and refluxed for 4 hours. The mixture was then cooled to 1'C and the pH
Add concentrated hydrochloric acid until the value reaches 2 (about 80 ml is required). Leave the mixture in an ice bath overnight. Concentrate under reduced pressure (
Bath temperature 20 ice) Remove ethanol. The resulting material is added (under N2 gas) to a cooled stirred suspension of 1 liter of water and 120 grams of NaHCO3. Extract the organic matter with 3 x 300 milliliters of ethyl acetate (excluding as much air as possible). The combined extracts are dried with MgSO4. This is filtered and concentrated under reduced pressure. Approximately 1 kg of the residue
Purification is performed by chromatography using iO2 (Baker) and ethyl acetate as the eluent. The corresponding fraction (
(determined by Tlc-EtOAc evolution) and concentrated to the appropriate volume to give the free base as white crystals. First harvest melting point 115-117 salt (33 grams), second harvest,
Melting point 114-116g (6 grams) Elemental analysis C9Hl
As INOS, calculated value: Cl59.66:Hl6. l2:Nl7.33
; Sll7,7 actual value: Cl59.64; Hl6.35
;Nl7.26:Sll7.3O This is converted into hydrochloride by the following method.

遊離塩基（３９グラム）を５００ミリリツトルの乾燥Ｔ
ＨＦ′に溶かし、攪拌下、乾燥ＨＣｌガスを２５℃以下
に保ちながら、わずかに過剰になるまで導入する。Free base (39 grams) in 500 milliliters of dry T.
Dissolve in HF' and introduce dry HCl gas under stirring, keeping the temperature below 25° C., until there is a slight excess.

出来た白色沈澱をｒ取し、テトラヒドロフランで洗浄し
真空下乾燥する。融点１４９１５２℃、Ｗｔ４５グラム
。元素分析 Ｃ９Ｈｌ２ＣｌＮＯＳとして、分子量２１
７．７計算値：Ｃｌ４９．６５：Ｈｌ５．５６：Ｎｌ６
，４４；Ｓｌｌ４．７３実測値：Ｃｌ４９．８７：Ｈｌ
５．８２；Ｎｌ６．４４；Ｓｌｌ５．ｌＯ参考例１で述
べた方法と本質的に同様な方法を用い、ここで用いた工
程Ａにおけるトリフエニルメチルホスホニウムブロマイ
ドの代りに当量のトリフエニルエチルホスホニウムブロ
マイド、トリフエニルベンジルホスホニウムブロマイド
、及びトリフエニルクロロメチルホスホニウムブロマイ
ド等を用いて、それぞれ連続に製する。The white precipitate formed is collected, washed with tetrahydrofuran, and dried under vacuum. Melting point: 149,152°C, Wt: 45 grams. Elemental analysis As C9Hl2ClNOS, molecular weight 21
7.7 Calculated value: Cl49.65: Hl5.56: Nl6
, 44; Sll4.73 actual value: Cl49.87:Hl
5.82;Nl6.44;Sll5. IO Using a method essentially similar to that described in Reference Example 1, instead of triphenylmethylphosphonium bromide in Step A used here, equivalent amounts of triphenylethylphosphonium bromide, triphenylbenzylphosphonium bromide, and triphenyl Each is produced continuously using chloromethylphosphonium bromide or the like.

工程Ａ：２−メチル−３−ヒドロキシ−４−ヒドロキシ
メチル−５−（１−プロベニル）−ピリジンの３・４α
−ジ一０−イソプロピリデン誘導体（油状物、３５パー
セント収率）；２−メチル−３−ヒドロキシ−４−ヒド
ロキシメチル−５−スチリルピリジンの３・４α−ジ一
０−イソプロピリデン誘導体。Step A: 3.4α of 2-methyl-3-hydroxy-4-hydroxymethyl-5-(1-probenyl)-pyridine
- Di10-isopropylidene derivative (oil, 35 percent yield); 3,4α-di10-isopropylidene derivative of 2-methyl-3-hydroxy-4-hydroxymethyl-5-styrylpyridine.

及び２−メチル−３−ヒドロキシ−４−ヒドロキシメチ
ル−５−（２−クロロビニル）ピリジンの３・４α−ジ
一０−イソプロピリデン誘導体。and 3,4α-di-10-isopropylidene derivatives of 2-methyl-3-hydroxy-4-hydroxymethyl-5-(2-chlorovinyl)pyridine.

工程Ｂ：２−メチル−３−ヒドロキシ−４−ヒドロキシ
メチル−５−（１−プロペニル）−ピリジン塩酸塩（１
００パーセント収率）２−メチル−３−ヒドロキシ−４
−ヒドロキシメチル−５−スチリルピリジン塩酸塩；及
び２−メチル−３−ヒドロキシ−４−ヒドロキシメチル
−５−（２−クロロビニル）ピリジン塩酸塩。Step B: 2-methyl-3-hydroxy-4-hydroxymethyl-5-(1-propenyl)-pyridine hydrochloride (1
00 percent yield) 2-methyl-3-hydroxy-4
-hydroxymethyl-5-styrylpyridine hydrochloride; and 2-methyl-3-hydroxy-4-hydroxymethyl-5-(2-chlorovinyl)pyridine hydrochloride.

工程Ｃ：２−メチル−３−ヒドロキシ−４−メルカプト
メチル−５−（−プロペニル）ピリジン塩酸塩（６０パ
ーセント収率、融点１７５ジ１７８℃）２−メチル−３
−ヒドロキシ−４−メルカプトメチル−５−スチリルピ
リジン塩酸塩（融点１９０−１９５℃）；及び２−メチ
ル−３−ヒドロキシ−４−メルカプトメチル−５−（２
−クロロビニル）ピリジン塩酸塩。Step C: 2-Methyl-3-hydroxy-4-mercaptomethyl-5-(-propenyl)pyridine hydrochloride (60 percent yield, mp 175°C) 2-methyl-3
-hydroxy-4-mercaptomethyl-5-styrylpyridine hydrochloride (melting point 190-195°C); and 2-methyl-3-hydroxy-4-mercaptomethyl-5-(2
-chlorovinyl)pyridine hydrochloride.

参考例 ２ ２−メチル−３−ヒドロキシ−４−メルカプトメチル−
５−ビニルピリジンのブンテ（Ｂｕｎｔｅ）塩工程Ａ：
２−メチル−３−ヒドロキシ−４−クロロメチル−５−
ビニルピリジン塩酸塩の作製１．６５グラムの２−メチ
ル−３−ヒドロキシ−４−ヒドロキシメチル−５−ビニ
ルピリジン塩酸塩、１ミリリツトルのチオニルクロライ
ド、２０ミリリツトルのテトラヒドロフランの混合物を
６時間還流する。Reference example 2 2-methyl-3-hydroxy-4-mercaptomethyl-
Bunte salt of 5-vinylpyridine Step A:
2-Methyl-3-hydroxy-4-chloromethyl-5-
Preparation of Vinylpyridine Hydrochloride A mixture of 1.65 grams of 2-methyl-3-hydroxy-4-hydroxymethyl-5-vinylpyridine hydrochloride, 1 milliliter of thionyl chloride, and 20 milliliters of tetrahydrofuran is refluxed for 6 hours.

冷却沈澱を▲取しエーテルで洗浄し乾燥して２−メチル
−３−ヒドロキシ−４−クロロメチル−５−ビニルピリ
ジン塩酸塩を与える。工程Ｂ：２−メチル−３−ヒドロ
キシ−４−メルカプトメチル−５−ビニルピリジンのブ
ンテ（ＢＵ］１ｔｅ）塩の作製２０グラムのナトリウム
チオスルフエート５水和物の１５ミリリツトル水溶液を
１８グラムの２一メチル一３−ヒドロキシ−４−クロロ
メチル−５−ビニルピリジン塩酸塩の５０パーセントエ
タノール１００ミリリツトル溶液に加える。The cooled precipitate is collected, washed with ether and dried to give 2-methyl-3-hydroxy-4-chloromethyl-5-vinylpyridine hydrochloride. Step B: Preparation of Bunte (BU]1te) salt of 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine. Add to a solution of 2-methyl-3-hydroxy-4-chloromethyl-5-vinylpyridine hydrochloride in 100 milliliters of 50 percent ethanol.

混合物を１時間７５℃に加熱し、冷却、溶媒留去して乾
燥し、２−メチル−３−ヒドロキシ−４−メルカプトメ
チル−５−ビニルピリジンのブンテ（Ｂｕｌｌｔｅ）塩
融点１９８−２００℃を与える。The mixture is heated to 75°C for 1 hour, cooled and evaporated to dryness to give the Bullte salt of 2-methyl-3-hydroxy-4-mercaptomethyl-5-vinylpyridine, mp 198-200°C. .

Claims (1)

【特許請求の範囲】 １ 下記式： ▲数式、化学式、表等があります▼ の化合物を空気又は酸素にさらすことを特徴とする式：
▲数式、化学式、表等があります▼ の化合物又はその薬剤的に有効な塩の製法。 ２ 下記式： ▲数式、化学式、表等があります▼ の化合物と酸化剤とを反応せしめることを特徴とする式
：▲数式、化学式、表等があります▼ の化合物又はその薬剤的に有効な塩の製法。 ３ 下記式： ▲数式、化学式、表等があります▼ の化合物を式： ▲数式、化学式、表等があります▼ とアルカリ性溶液中で加熱することを特徴とする式：▲
数式、化学式、表等があります▼ の化合物又はその薬剤的に有効な塩の製法。[Claims] 1. A formula characterized by exposing a compound of the following formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ to air or oxygen:
▲There are mathematical formulas, chemical formulas, tables, etc.▼ A method for producing the compound or its pharmaceutically effective salt. 2 The following formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ A formula characterized by reacting the compound of ▼ with an oxidizing agent: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ The compound or its pharmaceutically effective salt manufacturing method. 3 The formula below: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ The compound of: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ and the formula characterized by heating in an alkaline solution: ▲
There are mathematical formulas, chemical formulas, tables, etc. ▼ Process for producing the compound or its pharmaceutically effective salt.
JP49067656A 1973-06-15 1974-06-15 Method for producing bis[2-methyl-3-hydroxy-5-vinylpyrid-4-ylmethyl]disulfide Expired JPS59511B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US36877273A 1973-06-15 1973-06-15
US46177874A 1974-04-18 1974-04-18
US46401174A 1974-04-26 1974-04-26

Publications (2)

Publication Number Publication Date
JPS5040574A JPS5040574A (en) 1975-04-14
JPS59511B2 true JPS59511B2 (en) 1984-01-07

Family

ID=27408882

Family Applications (1)

Application Number Title Priority Date Filing Date
JP49067656A Expired JPS59511B2 (en) 1973-06-15 1974-06-15 Method for producing bis[2-methyl-3-hydroxy-5-vinylpyrid-4-ylmethyl]disulfide

Country Status (17)

Country Link
JP (1) JPS59511B2 (en)
CA (1) CA1021342A (en)
CH (1) CH605764A5 (en)
DE (1) DE2428470A1 (en)
DK (1) DK148594C (en)
EG (1) EG11578A (en)
ES (1) ES427187A1 (en)
FI (1) FI167474A (en)
FR (1) FR2233055B1 (en)
GB (1) GB1473591A (en)
IE (1) IE39896B1 (en)
IL (1) IL44958A (en)
LU (1) LU70318A1 (en)
NL (1) NL187395C (en)
NO (1) NO144569C (en)
SE (2) SE411208B (en)
ZM (1) ZM9274A1 (en)

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3290319A (en) * 1965-02-26 1966-12-06 Bristol Myers Co Substituted carbamates of pyridine 2, 6-dimethanethiols
US3591584A (en) * 1968-08-27 1971-07-06 Pfizer Benzothiazine dioxides
DE2161403A1 (en) * 1970-12-17 1972-07-06 Hidaka, Hiroyoshi, Nagoya, Aichi (Japan) Pyridine carbamate derivatives and processes for making the same

Also Published As

Publication number Publication date
DK148594C (en) 1986-01-27
GB1473591A (en) 1977-05-18
CA1021342A (en) 1977-11-22
IL44958A (en) 1978-09-29
DK290274A (en) 1975-02-10
FR2233055A1 (en) 1975-01-10
NL187395B (en) 1991-04-16
IL44958A0 (en) 1974-09-10
SE411208B (en) 1979-12-10
ZM9274A1 (en) 1976-02-23
FI167474A (en) 1974-12-16
NO144569C (en) 1981-09-23
CH605764A5 (en) 1978-10-13
AU6976574A (en) 1975-12-04
DE2428470A1 (en) 1975-01-23
NO144569B (en) 1981-06-15
DK148594B (en) 1985-08-12
IE39896B1 (en) 1979-01-31
FR2233055B1 (en) 1977-11-04
SE7711211L (en) 1977-10-06
DE2428470C2 (en) 1988-10-13
NL187395C (en) 1991-09-16
LU70318A1 (en) 1975-03-06
JPS5040574A (en) 1975-04-14
ES427187A1 (en) 1977-01-01
IE39896L (en) 1974-12-15
EG11578A (en) 1978-03-29
SE426170B (en) 1982-12-13
SE7406972L (en) 1974-12-16
NL7407212A (en) 1974-12-17
NO741962L (en) 1975-01-13

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